Abstract

The derivation and maintenance of hPSC in stable naïve pluripotent states has wide impact in human developmental biology. However, hPSC are unstable in classical naïve mouse ESC WNT and MEK/ERK signal inhibition (2i) culture. We show that a broad repertoire of conventional human embryonic stem cell (hESC) and transgene-independent hiPSC lines could be reverted to stable human preimplantation ICM-like naïve states with only WNT, MEK/ERK, and tankyrase inhibition (LIF-3i). LIF-3i-reverted hPSC retained normal karyotypes and attained defining mouse ESC-like functional features including high clonal self-renewal, independence from MEK-ERK signalling, dependence on JAK-STAT3 and BMP4 signaling, and naïve-specific transcriptional and epigenetic configurations. Tankyrase inhibition promoted a stable acquisition of a human preimplantation ICM-like ground state via modulation of WNT signalling, and was most efficacious in efficiently reprogrammed conventional hiPSC. Importantly, naïve reversion of a broad repertoire of conventional hiPSC reduced lineage-primed gene expression, and significantly improved their multi-lineage differentiation capacities. Stable naïve hPSC with reduced genetic variability and improved functional pluripotency will have great utility in regenerative medicine and human disease modeling.

Received June 6, 2016.

Accepted September 11, 2016.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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